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Mostafa M, Disouky A, Lazarov O. Therapeutic modulation of neurogenesis to improve hippocampal plasticity and cognition in aging and Alzheimer's disease. Neurotherapeutics 2025; 22:e00580. [PMID: 40180804 PMCID: PMC12047516 DOI: 10.1016/j.neurot.2025.e00580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/14/2025] [Accepted: 03/17/2025] [Indexed: 04/05/2025] Open
Abstract
Alzheimer's disease is characterized by progressive memory loss and cognitive decline. The hippocampal formation is the most vulnerable brain area in Alzheimer's disease. Neurons in layer II of the entorhinal cortex and the CA1 region of the hippocampus are lost at early stages of the disease. A unique feature of the hippocampus is the formation of new neurons that incorporate in the dentate gyrus of the hippocampus. New neurons form synapses with neurons in layer II of the entorhinal cortex and with the CA3 region. Immature and new neurons are characterized by high level of plasticity. They play important roles in learning and memory. Hippocampal neurogenesis is impaired early in mouse models of Alzheimer's disease and in human patients. In fact, neurogenesis is compromised in mild cognitive impairment (MCI), suggesting that rescuing neurogenesis may restore hippocampal plasticity and attenuate neuronal vulnerability and memory loss. This review will discuss the current understanding of therapies that target neurogenesis or modulate it, for the treatment of Alzheimer's disease.
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Affiliation(s)
- Mostafa Mostafa
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Ahmed Disouky
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Orly Lazarov
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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2
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Liang Z, Jin N, Guo W. Neural stem cell heterogeneity in adult hippocampus. CELL REGENERATION (LONDON, ENGLAND) 2025; 14:6. [PMID: 40053275 DOI: 10.1186/s13619-025-00222-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 02/07/2025] [Accepted: 02/11/2025] [Indexed: 03/10/2025]
Abstract
Adult neurogenesis is a unique cellular process of the ongoing generation of new neurons throughout life, which primarily occurs in the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricle. In the adult DG, newly generated granule cells from neural stem cells (NSCs) integrate into existing neural circuits, significantly contributing to cognitive functions, particularly learning and memory. Recently, more and more studies have shown that rather than being a homogeneous population of identical cells, adult NSCs are composed of multiple subpopulations that differ in their morphology and function. In this study, we provide an overview of the origin, regional characteristics, prototypical morphology, and molecular factors that contribute to NSC heterogeneity. In particular, we discuss the molecular mechanisms underlying the balance between activation and quiescence of NSCs. In summary, this review highlights that deciphering NSC heterogeneity in the adult brain is a challenging but critical step in advancing our understanding of tissue-specific stem cells and the process of neurogenesis in the adult brain.
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Affiliation(s)
- Ziqi Liang
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100093, China
| | - Nuomeng Jin
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100093, China
| | - Weixiang Guo
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100093, China.
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3
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Chouly M, Bally-Cuif L. Generating neurons in the embryonic and adult brain: compared principles and mechanisms. C R Biol 2024; 347:199-221. [PMID: 39535540 DOI: 10.5802/crbiol.167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/06/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024]
Abstract
Neurogenesis is a lifelong process, generating neurons in the right amount, time and place and with the correct identity to permit the growth, function, plasticity and repair of the nervous system, notably the brain. Neurogenesis originates from neural progenitor cells (NPs), endowed with the capacity to divide, renew to maintain the progenitor population, or commit to engage in the neurogenesis process. In the adult brain, these progenitors are classically called neural stem cells (NSCs). We review here the commonalities and differences between NPs and NSCs, in their cellular and molecular attributes but also in their potential, regulators and lineage, in the embryonic and adult brains. Our comparison is based on the two most studied model systems, namely the telencephalon of the zebrafish and mouse. We also discuss how the population of embryonic NPs gives rise to adult NSCs, and outstanding questions pertaining to this transition.
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Chen X, Huang Y, Huang L, Huang Z, Hao ZZ, Xu L, Xu N, Li Z, Mou Y, Ye M, You R, Zhang X, Liu S, Miao Z. A brain cell atlas integrating single-cell transcriptomes across human brain regions. Nat Med 2024; 30:2679-2691. [PMID: 39095595 PMCID: PMC11405287 DOI: 10.1038/s41591-024-03150-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 06/24/2024] [Indexed: 08/04/2024]
Abstract
While single-cell technologies have greatly advanced our comprehension of human brain cell types and functions, studies including large numbers of donors and multiple brain regions are needed to extend our understanding of brain cell heterogeneity. Integrating atlas-level single-cell data presents a chance to reveal rare cell types and cellular heterogeneity across brain regions. Here we present the Brain Cell Atlas, a comprehensive reference atlas of brain cells, by assembling single-cell data from 70 human and 103 mouse studies of the brain throughout major developmental stages across brain regions, covering over 26.3 million cells or nuclei from both healthy and diseased tissues. Using machine-learning based algorithms, the Brain Cell Atlas provides a consensus cell type annotation, and it showcases the identification of putative neural progenitor cells and a cell subpopulation of PCDH9high microglia in the human brain. We demonstrate the gene regulatory difference of PCDH9high microglia between hippocampus and prefrontal cortex and elucidate the cell-cell communication network. The Brain Cell Atlas presents an atlas-level integrative resource for comparing brain cells in different environments and conditions within the Human Cell Atlas.
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Affiliation(s)
- Xinyue Chen
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, China
| | - Yin Huang
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, China
| | - Liangfeng Huang
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, China
| | - Ziliang Huang
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, China
| | - Zhao-Zhe Hao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Lahong Xu
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, China
| | - Nana Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Zhi Li
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yonggao Mou
- Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Mingli Ye
- Tsinghua Fuzhou Institute for Data Technology, Fuzhou, China
| | - Renke You
- Tsinghua Fuzhou Institute for Data Technology, Fuzhou, China
| | - Xuegong Zhang
- MOE Key Lab of Bioinformatics, Bioinformatics Division of BNRIST and Department of Automation, Tsinghua University, Beijing, China
- School of Medicine, Tsinghua University, Beijing, China
- School of Life Sciences, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Sheng Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
- Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, China.
| | - Zhichao Miao
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou International Bio Island, Guangzhou, China.
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou International Bio Island, Guangzhou, China.
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Deng X, Hu Z, Zhou S, Wu Y, Fu M, Zhou C, Sun J, Gao X, Huang Y. Perspective from single-cell sequencing: Is inflammation in acute ischemic stroke beneficial or detrimental? CNS Neurosci Ther 2024; 30:e14510. [PMID: 37905592 PMCID: PMC10805403 DOI: 10.1111/cns.14510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/24/2023] [Accepted: 10/08/2023] [Indexed: 11/02/2023] Open
Abstract
BACKGROUND Acute ischemic stroke (AIS) is a common cerebrovascular event associated with high incidence, disability, and poor prognosis. Studies have shown that various cell types, including microglia, astrocytes, oligodendrocytes, neurons, and neutrophils, play complex roles in the early stages of AIS and significantly affect its prognosis. Thus, a comprehensive understanding of the mechanisms of action of these cells will be beneficial for improving stroke prognosis. With the rapid development of single-cell sequencing technology, researchers have explored the pathophysiological mechanisms underlying AIS at the single-cell level. METHOD We systematically summarize the latest research on single-cell sequencing in AIS. RESULT In this review, we summarize the phenotypes and functions of microglia, astrocytes, oligodendrocytes, neurons, neutrophils, monocytes, and lymphocytes, as well as their respective subtypes, at different time points following AIS. In particular, we focused on the crosstalk between microglia and astrocytes, oligodendrocytes, and neurons. Our findings reveal diverse and sometimes opposing roles within the same cell type, with the possibility of interconversion between different subclusters. CONCLUSION This review offers a pioneering exploration of the functions of various glial cells and cell subclusters after AIS, shedding light on their regulatory mechanisms that facilitate the transformation of detrimental cell subclusters towards those that are beneficial for improving the prognosis of AIS. This approach has the potential to advance the discovery of new specific targets and the development of drugs, thus representing a significant breakthrough in addressing the challenges in AIS treatment.
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Affiliation(s)
- Xinpeng Deng
- Department of NeurosurgeryThe First Affiliated Hospital of Ningbo UniversityNingboChina
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang ProvinceNingboChina
| | - Ziliang Hu
- Department of NeurosurgeryThe First Affiliated Hospital of Ningbo UniversityNingboChina
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang ProvinceNingboChina
| | - Shengjun Zhou
- Department of NeurosurgeryThe First Affiliated Hospital of Ningbo UniversityNingboChina
| | - Yiwen Wu
- Department of NeurosurgeryThe First Affiliated Hospital of Ningbo UniversityNingboChina
| | - Menglin Fu
- School of Economics and ManagementChina University of GeosciencesWuhanChina
| | - Chenhui Zhou
- Department of NeurosurgeryThe First Affiliated Hospital of Ningbo UniversityNingboChina
| | - Jie Sun
- Department of NeurosurgeryThe First Affiliated Hospital of Ningbo UniversityNingboChina
| | - Xiang Gao
- Department of NeurosurgeryThe First Affiliated Hospital of Ningbo UniversityNingboChina
| | - Yi Huang
- Department of NeurosurgeryThe First Affiliated Hospital of Ningbo UniversityNingboChina
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang ProvinceNingboChina
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6
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Pinatel D, Pearlstein E, Bonetto G, Goutebroze L, Karagogeos D, Crepel V, Faivre-Sarrailh C. A class-specific effect of dysmyelination on the excitability of hippocampal interneurons. eLife 2023; 12:e86469. [PMID: 37843188 PMCID: PMC10617988 DOI: 10.7554/elife.86469] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 10/13/2023] [Indexed: 10/17/2023] Open
Abstract
The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin (PV) and somatostatin (SST) neurons, two major classes of GABAergic neurons in the hippocampus. We show that 4.1B-deficiency induces disruption of juxtaparanodal K+ channel clustering and mislocalization of nodal or heminodal Na+ channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens SST cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking PV cells do not appear affected. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive.
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Affiliation(s)
| | | | | | - Laurence Goutebroze
- INSERM, Institut du Fer à Moulin, Sorbonne Université, Faculté des Sciences et IngénierieParisFrance
| | - Domna Karagogeos
- Department of Basic Sciences, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, University of CreteHeraklionGreece
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Jiménez Peinado P, Urbach A. From Youthful Vigor to Aging Decline: Unravelling the Intrinsic and Extrinsic Determinants of Hippocampal Neural Stem Cell Aging. Cells 2023; 12:2086. [PMID: 37626896 PMCID: PMC10453598 DOI: 10.3390/cells12162086] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/15/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Since Joseph Altman published his pioneering work demonstrating neurogenesis in the hippocampus of adult rats, the number of publications in this field increased exponentially. Today, we know that the adult hippocampus harbors a pool of adult neural stem cells (NSCs) that are the source of life-long neurogenesis and plasticity. The functions of these NSCs are regulated by extrinsic cues arising from neighboring cells and the systemic environment. However, this tight regulation is subject to imbalance with age, resulting in a decline in adult NSCs and neurogenesis, which contributes to the progressive deterioration of hippocampus-related cognitive functions. Despite extensive investigation, the mechanisms underlying this age-related decline in neurogenesis are only incompletely understood, but appear to include an increase in NSC quiescence, changes in differentiation patterns, and NSC exhaustion. In this review, we summarize recent work that has improved our knowledge of hippocampal NSC aging, focusing on NSC-intrinsic mechanisms as well as cellular and molecular changes in the niche and systemic environment that might be involved in the age-related decline in NSC functions. Additionally, we identify future directions that may advance our understanding of NSC aging and the concomitant loss of hippocampal neurogenesis and plasticity.
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Affiliation(s)
| | - Anja Urbach
- Department of Neurology, Jena University Hospital, 07747 Jena, Germany
- Jena Center for Healthy Aging, Jena University Hospital, 07747 Jena, Germany
- Aging Research Center Jena, Leibniz Institute on Aging, 07745 Jena, Germany
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8
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Bai X, Zhao N, Koupourtidou C, Fang LP, Schwarz V, Caudal LC, Zhao R, Hirrlinger J, Walz W, Bian S, Huang W, Ninkovic J, Kirchhoff F, Scheller A. In the mouse cortex, oligodendrocytes regain a plastic capacity, transforming into astrocytes after acute injury. Dev Cell 2023:S1534-5807(23)00192-2. [PMID: 37220747 DOI: 10.1016/j.devcel.2023.04.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 02/16/2023] [Accepted: 04/25/2023] [Indexed: 05/25/2023]
Abstract
Acute brain injuries evoke various response cascades directing the formation of the glial scar. Here, we report that acute lesions associated with hemorrhagic injuries trigger a re-programming of oligodendrocytes. Single-cell RNA sequencing highlighted a subpopulation of oligodendrocytes activating astroglial genes after acute brain injuries. By using PLP-DsRed1/GFAP-EGFP and PLP-EGFPmem/GFAP-mRFP1 transgenic mice, we visualized this population of oligodendrocytes that we termed AO cells based on their concomitant activity of astro- and oligodendroglial genes. By fate mapping using PLP- and GFAP-split Cre complementation and repeated chronic in vivo imaging with two-photon laser-scanning microscopy, we observed the conversion of oligodendrocytes into astrocytes via the AO cell stage. Such conversion was promoted by local injection of IL-6 and was diminished by IL-6 receptor-neutralizing antibody as well as by inhibiting microglial activation with minocycline. In summary, our findings highlight the plastic potential of oligodendrocytes in acute brain trauma due to microglia-derived IL-6.
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Affiliation(s)
- Xianshu Bai
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany.
| | - Na Zhao
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Christina Koupourtidou
- Department of Cell Biology and Anatomy, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Institute of Stem Cell Research, Helmholtz Zentrum Munich, 85764 Neuherberg-Munich, Germany
| | - Li-Pao Fang
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Veronika Schwarz
- Department of Cell Biology and Anatomy, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Institute of Stem Cell Research, Helmholtz Zentrum Munich, 85764 Neuherberg-Munich, Germany
| | - Laura C Caudal
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Renping Zhao
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Johannes Hirrlinger
- Carl-Ludwig-Institute for Physiology, Leipzig University, 04103 Leipzig, Germany; Department of Neurogenetics, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Germany
| | - Wolfgang Walz
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany; Department of Psychiatry, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada
| | - Shan Bian
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 200092 Shanghai, China; Frontier Science Center for Stem Cell Research, Tongji University, 200092 Shanghai, China
| | - Wenhui Huang
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Jovica Ninkovic
- Department of Cell Biology and Anatomy, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Institute of Stem Cell Research, Helmholtz Zentrum Munich, 85764 Neuherberg-Munich, Germany
| | - Frank Kirchhoff
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany; Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anja Scheller
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany.
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Meng H, Li Q, Wang J, Yue W, Zhang D, Sun X, Wang L, Li J. The expansion of newborn neurons in hippocampus improves social recognition deficit in a mouse model of autism. Front Psychiatry 2023; 14:1162179. [PMID: 37215664 PMCID: PMC10196005 DOI: 10.3389/fpsyt.2023.1162179] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 04/10/2023] [Indexed: 05/24/2023] Open
Abstract
Introduction Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by core symptoms of impaired social interaction and communication. The pathological mechanism and treatment are not clear and need further study. Our previous study found that the deletion of high-risk gene Autism Susceptibility 2 (AUTS2) in mice led to dentate gyrus (DG) hypoplasia that highly associated with impaired social novelty recognition. Here we aim to improve the social deficit through increasing the neurogenesis in the subgranular zone (SGZ) and expanding the newborn granule neurons in DG. Methods Three approaches including repeated oxytocin administration, feeding in enriched environment and overexpression of cyclin-dependent kinase 4 (Cdk4)-CyclinD1 complex in DG neural stem cells (NSCs) at the post-weaning stage were conducted. Results We found that the number of EdU labeled proliferative NSCs or retrovirus labeled newborn neurons was significantly increased after manipulations. The social recognition deficit was also significantly improved. Discussion Our findings suggested a possible strategy to restore the social deficit through expansion of newborn neurons in hippocampus, which might provide a new insight into the treatment of autism.
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Affiliation(s)
- Hu Meng
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Qiongwei Li
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Jinxin Wang
- State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
| | - Weihua Yue
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Dai Zhang
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
- Institute for Brain Research and Rehabilitation (IBRR), Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, China
| | - Xiaoxuan Sun
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Lifang Wang
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Jun Li
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
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10
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von Berlin L, Westholm JO, Ratz M, Frisén J. Early fate bias in neuroepithelial progenitors of hippocampal neurogenesis. Hippocampus 2023; 33:391-401. [PMID: 36468233 DOI: 10.1002/hipo.23482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/17/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022]
Abstract
Hippocampal adult neural stem cells emerge from progeny of the neuroepithelial lineage during murine brain development. Hippocampus development is increasingly well understood. However, the clonal relationships between early neuroepithelial stem cells and postnatal neurogenic cells remain unclear, especially at the single-cell level. Here we report fate bias and gene expression programs in thousands of clonally related cells in the juvenile hippocampus based on single-cell RNA-seq of barcoded clones. We find evidence for early fate restriction of neuroepithelial stem cells to either neurogenic progenitor cells of the dentate gyrus region or oligodendrogenic, non-neurogenic fate supplying cells for other hippocampal regions including gray matter areas and the Cornu ammonis region 1/3. Our study provides new insights into the phenomenon of early fate restriction guiding the development of postnatal hippocampal neurogenesis.
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Affiliation(s)
- Leonie von Berlin
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
| | - Jakub Orzechowski Westholm
- Department of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Stockholm University, Solna, Sweden
| | - Michael Ratz
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
- KTH Royal Institute of Technology, Department of Gene Technology, Stockholm, Sweden
| | - Jonas Frisén
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
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11
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Galante C, Marichal N, Scarante FF, Ghayad LM, Shi Y, Schuurmans C, Berninger B, Péron S. Enhanced proliferation of oligodendrocyte progenitor cells following retrovirus mediated Achaete-scute complex-like 1 overexpression in the postnatal cerebral cortex in vivo. Front Neurosci 2022; 16:919462. [PMID: 36532282 PMCID: PMC9755855 DOI: 10.3389/fnins.2022.919462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 11/09/2022] [Indexed: 12/03/2022] Open
Abstract
The proneural transcription factor Achaete-scute complex-like 1 (Ascl1) is a major regulator of neural fate decisions, implicated both in neurogenesis and oligodendrogliogenesis. Focusing on its neurogenic activity, Ascl1 has been widely used to reprogram non-neuronal cells into induced neurons. In vitro, Ascl1 induces efficient reprogramming of proliferative astroglia from the early postnatal cerebral cortex into interneuron-like cells. Here, we examined whether Ascl1 can similarly induce neuronal reprogramming of glia undergoing proliferation in the postnatal mouse cerebral cortex in vivo. Toward this goal, we targeted cortical glia during the peak of proliferative expansion (i.e., postnatal day 5) by injecting a retrovirus encoding for Ascl1 into the mouse cerebral cortex. In contrast to the efficient reprogramming observed in vitro, in vivo Ascl1-transduced glial cells were converted into doublecortin-immunoreactive neurons only with very low efficiency. However, we noted a drastic shift in the relative number of retrovirus-transduced Sox10-positive oligodendrocyte progenitor cells (OPCs) as compared to glial fibrillary acidic protein (GFAP)-positive astrocytes. Genetic fate mapping demonstrated that this increase in OPCs was not due to Ascl1-mediated astrocyte-to-OPC fate conversion. Rather, EdU incorporation experiments revealed that Ascl1 caused a selective increase in proliferative activity of OPCs, but not astrocytes. Our data indicate that rather than inducing neuronal reprogramming of glia in the early postnatal cortex, Ascl1 is a selective enhancer of OPC proliferation.
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Affiliation(s)
- Chiara Galante
- Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University, Mainz, Germany
| | - Nicolás Marichal
- Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
| | - Franciele Franco Scarante
- Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom,Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Litsa Maria Ghayad
- Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
| | - Youran Shi
- Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom,The Francis Crick Institute, London, United Kingdom
| | - Carol Schuurmans
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada,Department of Biochemistry, University of Toronto, Toronto, ON, Canada,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Benedikt Berninger
- Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University, Mainz, Germany,Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom,The Francis Crick Institute, London, United Kingdom,MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom,Focus Program Translational Neuroscience, Johannes Gutenberg University, Mainz, Germany,Benedikt Berninger,
| | - Sophie Péron
- Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University, Mainz, Germany,Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom,*Correspondence: Sophie Péron,
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12
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Lee DG, Kim YK, Baek KH. The bHLH Transcription Factors in Neural Development and Therapeutic Applications for Neurodegenerative Diseases. Int J Mol Sci 2022; 23:ijms232213936. [PMID: 36430421 PMCID: PMC9696289 DOI: 10.3390/ijms232213936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
The development of functional neural circuits in the central nervous system (CNS) requires the production of sufficient numbers of various types of neurons and glial cells, such as astrocytes and oligodendrocytes, at the appropriate periods and regions. Hence, severe neuronal loss of the circuits can cause neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Treatment of such neurodegenerative diseases caused by neuronal loss includes some strategies of cell therapy employing stem cells (such as neural progenitor cells (NPCs)) and gene therapy through cell fate conversion. In this report, we review how bHLH acts as a regulator in neuronal differentiation, reprogramming, and cell fate determination. Moreover, several different researchers are conducting studies to determine the importance of bHLH factors to direct neuronal and glial cell fate specification and differentiation. Therefore, we also investigated the limitations and future directions of conversion or transdifferentiation using bHLH factors.
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Affiliation(s)
- Dong Gi Lee
- Joint Section of Science in Environmental Technology, Food Technology, and Molecular Biotechnology, Ghent University, Incheon 21569, Korea
| | - Young-Kwang Kim
- Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam 13488, Korea
| | - Kwang-Hyun Baek
- Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam 13488, Korea
- Correspondence: ; Tel.: +82-31-881-7134
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13
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Jiménez S, Moreno N. Development of subdomains in the medial pallium of Xenopus laevis and Trachemys scripta: Insights into the anamniote-amniote transition. Front Neuroanat 2022; 16:1039081. [PMID: 36406242 PMCID: PMC9670315 DOI: 10.3389/fnana.2022.1039081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
In all vertebrates, the most dorsal region of the telencephalon gives rise to the pallium, which in turn, is formed by at least four evolutionarily conserved histogenetic domains. Particularly in mammals, the medial pallium generates the hippocampal formation. Although this region is structurally different among amniotes, its functions, attributed to spatial memory and social behavior, as well as the specification of the histogenetic domain, appears to be conserved. Thus, the aim of the present study was to analyze this region by comparative analysis of the expression patterns of conserved markers in two vertebrate models: one anamniote, the amphibian Xenopus laevis; and the other amniote, the turtle Trachemys scripta elegans, during development and in adulthood. Our results show that, the histogenetic specification of both models is comparable, despite significant cytoarchitectonic differences, in particular the layered cortical arrangement present in the turtle, not found in anurans. Two subdivisions were observed in the medial pallium of these species: a Prox1 + and another Er81/Lmo4 +, comparable to the dentate gyrus and the mammalian cornu ammonis region, respectively. The expression pattern of additional markers supports this subdivision, which together with its functional involvement in spatial memory tasks, provides evidence supporting the existence of a basic program in the specification and functionality of the medial pallium at the base of tetrapods. These results further suggest that the anatomical differences found in different vertebrates may be due to divergences and adaptations during evolution.
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Affiliation(s)
| | - Nerea Moreno
- *Correspondence: Nerea Moreno, , orcid.org/0000-0002-5578-192X
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14
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McNerlin C, Guan F, Bronk L, Lei K, Grosshans D, Young DW, Gaber MW, Maletic-Savatic M. Targeting hippocampal neurogenesis to protect astronauts' cognition and mood from decline due to space radiation effects. LIFE SCIENCES IN SPACE RESEARCH 2022; 35:170-179. [PMID: 36336363 DOI: 10.1016/j.lssr.2022.07.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/30/2022] [Accepted: 07/26/2022] [Indexed: 06/16/2023]
Abstract
Neurogenesis is an essential, lifelong process during which neural stem cells generate new neurons within the hippocampus, a center for learning, memory, and mood control. Neural stem cells are vulnerable to environmental insults spanning from chronic stress to radiation. These insults reduce their numbers and diminish neurogenesis, leading to memory decline, anxiety, and depression. Preserving neural stem cells could thus help prevent these neurogenesis-associated pathologies, an outcome particularly important for long-term space missions where environmental exposure to radiation is significantly higher than on Earth. Multiple developments, from mechanistic discoveries of radiation injury on hippocampal neurogenesis to new platforms for the development of selective, specific, effective, and safe small molecules as neurogenesis-protective agents hold great promise to minimize radiation damage on neurogenesis. In this review, we summarize the effects of space-like radiation on hippocampal neurogenesis. We then focus on current advances in drug discovery and development and discuss the nuclear receptor TLX/NR2E1 (oleic acid receptor) as an example of a neurogenic target that might rescue neurogenesis following radiation.
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Affiliation(s)
- Clare McNerlin
- Georgetown University School of Medicine, 3900 Reservoir Rd NW, Washington D.C. 20007, United States of America
| | - Fada Guan
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, 06510, United States of America
| | - Lawrence Bronk
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States of America
| | - Kevin Lei
- Graduate School for Biomedical Sciences, Baylor College of Medicine, Houston, Texas, 77030, United States of America; Jan and Dan Duncan Neurological Research Institute, 1250 Moursund St. Houston, TX 77030, United States of America
| | - David Grosshans
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States of America
| | - Damian W Young
- Jan and Dan Duncan Neurological Research Institute, 1250 Moursund St. Houston, TX 77030, United States of America; Center for Drug Discovery, Department of Pathology and Immunology Baylor College of Medicine, Houston, Texas, 77030, United States of America; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States of America
| | - M Waleed Gaber
- Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States of America.
| | - Mirjana Maletic-Savatic
- Jan and Dan Duncan Neurological Research Institute, 1250 Moursund St. Houston, TX 77030, United States of America; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States of America; Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States of America.
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15
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Tanabe K, Nobuta H, Yang N, Ang CE, Huie P, Jordan S, Oldham MC, Rowitch DH, Wernig M. Generation of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion. Development 2022; 149:275808. [PMID: 35748297 PMCID: PMC9357374 DOI: 10.1242/dev.199723] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 05/03/2022] [Indexed: 01/08/2023]
Abstract
Oligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols ( Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts.
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Affiliation(s)
- Koji Tanabe
- I Peace, Inc, Palo Alto, CA 94303, USA.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hiroko Nobuta
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143, USA
| | - Nan Yang
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Cheen Euong Ang
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Philip Huie
- Department of Surgical Pathology, Stanford Health Care, Palo Alto, CA 94305, USA
| | - Sacha Jordan
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854, USA
| | - Michael C Oldham
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143, USA.,Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - David H Rowitch
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143, USA.,Departments of Pediatrics and Neurosurgery, University of California San Francisco, San Francisco, CA 94143, USA.,Department of Paediatrics and Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK
| | - Marius Wernig
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
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16
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Rodríguez-Bodero A, Encinas-Pérez JM. Does the plasticity of neural stem cells and neurogenesis make them biosensors of disease and damage? Front Neurosci 2022; 16:977209. [PMID: 36161150 PMCID: PMC9493188 DOI: 10.3389/fnins.2022.977209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/15/2022] [Indexed: 11/29/2022] Open
Abstract
Postnatal and adult neurogenesis takes place in the dentate gyrus of the hippocampus in the vast majority of mammals due to the persistence of a population of neural stem cells (NSCs) that also generate astrocytes and more NSCs. These are highly plastic and dynamic phenomena that undergo continuous modifications in response to the changes brain homeostasis. The properties of NSCs as well as the process of neurogenesis and gliogenesis, are reshaped divergently by changes in neuronal activity and by different types of disease and damage. This richness of plastic responses identifies NSCs and newborn neurons as biosensors of the health state of the hippocampus, detecting and providing useful information about processes such as neuronal and network hyperexcitation, excitotoxicity, neurodegeneration, and neuroinflammation. Learning to gather and use this information is a challenge worth of our attention.
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Affiliation(s)
- Ane Rodríguez-Bodero
- The Neural Stem Cells and Neurogenesis Lab, Achucarro Basque Center for Neuroscience, Leioa, Spain
- Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Juan Manuel Encinas-Pérez
- The Neural Stem Cells and Neurogenesis Lab, Achucarro Basque Center for Neuroscience, Leioa, Spain
- Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Spain
- IKERBASQUE, The Basque Foundation for Science, Bilbao, Spain
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17
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Mol P, Gopalakrishnan L, Chatterjee O, Mangalaparthi KK, Kumar M, Durgad SS, Nair B, Shankar SK, Mahadevan A, Prasad TSK. Proteomic Analysis of Adult Human Hippocampal Subfields Demonstrates Regional Heterogeneity in the Protein Expression. J Proteome Res 2022; 21:2293-2310. [PMID: 36039803 DOI: 10.1021/acs.jproteome.2c00143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Background: Distinct hippocampal subfields are known to get affected during aging, psychiatric disorders, and various neurological and neurodegenerative conditions. To understand the biological processes associated with each subfield, it is important to understand its heterogeneity at the molecular level. To address this lacuna, we investigated the proteomic analysis of hippocampal subfields─the cornu ammonis sectors (CA1, CA2, CA3, CA4) and dentate gyrus (DG) from healthy adult human cohorts. Findings: Microdissection of hippocampal subfields from archived formalin-fixed paraffin-embedded tissue sections followed by TMT-based multiplexed proteomic analysis resulted in the identification of 5,593 proteins. Out of these, 890 proteins were found to be differentially abundant among the subfields. Further bioinformatics analysis suggested proteins related to gene splicing, transportation, myelination, structural activity, and learning processes to be differentially abundant in DG, CA4, CA3, CA2, and CA1, respectively. A subset of proteins was selected for immunohistochemistry-based validation in an independent set of hippocampal samples. Conclusions: We believe that our findings will effectively pave the way for further analysis of the hippocampal subdivisions and provide awareness of its subfield-specific association to various neurofunctional anomalies in the future. The current mass spectrometry data is deposited and publicly made available through ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD029697.
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Affiliation(s)
- Praseeda Mol
- Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore 560066,India.,Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 690525, India
| | - Lathika Gopalakrishnan
- Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore 560066,India.,Centre for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India.,Manipal Academy of Higher Education, Manipal 576104, India
| | - Oishi Chatterjee
- Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore 560066,India.,Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 690525, India.,Centre for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
| | - Kiran K Mangalaparthi
- Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore 560066,India.,Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 690525, India
| | - Manish Kumar
- Institute of Bioinformatics, International Technology Park, Whitefield, Bangalore 560066,India.,Manipal Academy of Higher Education, Manipal 576104, India
| | - Shwetha S Durgad
- Human Brain Tissue Repository, National Institute of Mental Health and Neurosciences, Bangalore 560029, India
| | - Bipin Nair
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 690525, India
| | - Susarla K Shankar
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India.,Human Brain Tissue Repository, National Institute of Mental Health and Neurosciences, Bangalore 560029, India
| | - Anita Mahadevan
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India.,Human Brain Tissue Repository, National Institute of Mental Health and Neurosciences, Bangalore 560029, India
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18
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Ghazale H, Park E, Vasan L, Mester J, Saleh F, Trevisiol A, Zinyk D, Chinchalongporn V, Liu M, Fleming T, Prokopchuk O, Klenin N, Kurrasch D, Faiz M, Stefanovic B, McLaurin J, Schuurmans C. Ascl1 phospho-site mutations enhance neuronal conversion of adult cortical astrocytes in vivo. Front Neurosci 2022; 16:917071. [PMID: 36061596 PMCID: PMC9434350 DOI: 10.3389/fnins.2022.917071] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Direct neuronal reprogramming, the process whereby a terminally differentiated cell is converted into an induced neuron without traversing a pluripotent state, has tremendous therapeutic potential for a host of neurodegenerative diseases. While there is strong evidence for astrocyte-to-neuron conversion in vitro, in vivo studies in the adult brain are less supportive or controversial. Here, we set out to enhance the efficacy of neuronal conversion of adult astrocytes in vivo by optimizing the neurogenic capacity of a driver transcription factor encoded by the proneural gene Ascl1. Specifically, we mutated six serine phospho-acceptor sites in Ascl1 to alanines (Ascl1 SA 6) to prevent phosphorylation by proline-directed serine/threonine kinases. Native Ascl1 or Ascl1 SA 6 were expressed in adult, murine cortical astrocytes under the control of a glial fibrillary acidic protein (GFAP) promoter using adeno-associated viruses (AAVs). When targeted to the cerebral cortex in vivo, mCherry+ cells transduced with AAV8-GFAP-Ascl1 SA 6-mCherry or AAV8-GFAP-Ascl1-mCherry expressed neuronal markers within 14 days post-transduction, with Ascl1 SA 6 promoting the formation of more mature dendritic arbors compared to Ascl1. However, mCherry expression disappeared by 2-months post-transduction of the AAV8-GFAP-mCherry control-vector. To circumvent reporter issues, AAV-GFAP-iCre (control) and AAV-GFAP-Ascl1 (or Ascl1 SA 6)-iCre constructs were generated and injected into the cerebral cortex of Rosa reporter mice. In all comparisons of AAV capsids (AAV5 and AAV8), GFAP promoters (long and short), and reporter mice (Rosa-zsGreen and Rosa-tdtomato), Ascl1 SA 6 transduced cells more frequently expressed early- (Dcx) and late- (NeuN) neuronal markers. Furthermore, Ascl1 SA 6 repressed the expression of astrocytic markers Sox9 and GFAP more efficiently than Ascl1. Finally, we co-transduced an AAV expressing ChR2-(H134R)-YFP, an optogenetic actuator. After channelrhodopsin photostimulation, we found that Ascl1 SA 6 co-transduced astrocytes exhibited a significantly faster decay of evoked potentials to baseline, a neuronal feature, when compared to iCre control cells. Taken together, our findings support an enhanced neuronal conversion efficiency of Ascl1 SA 6 vs. Ascl1, and position Ascl1 SA 6 as a critical transcription factor for future studies aimed at converting adult brain astrocytes to mature neurons to treat disease.
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Affiliation(s)
- Hussein Ghazale
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - EunJee Park
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Lakshmy Vasan
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - James Mester
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Fermisk Saleh
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Andrea Trevisiol
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Dawn Zinyk
- Sunnybrook Research Institute, Toronto, ON, Canada
| | - Vorapin Chinchalongporn
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Mingzhe Liu
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Taylor Fleming
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | | | - Natalia Klenin
- Department of Medical Genetics, Cumming School of Medicine, Hotchkiss Brain Institute, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Deborah Kurrasch
- Department of Medical Genetics, Cumming School of Medicine, Hotchkiss Brain Institute, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Maryam Faiz
- Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Bojana Stefanovic
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - JoAnne McLaurin
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Carol Schuurmans
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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19
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Endogenous Neural Stem Cell Mediated Oligodendrogenesis in the Adult Mammalian Brain. Cells 2022; 11:cells11132101. [PMID: 35805185 PMCID: PMC9265817 DOI: 10.3390/cells11132101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 02/08/2023] Open
Abstract
Oligodendrogenesis is essential for replacing worn-out oligodendrocytes, promoting myelin plasticity, and for myelin repair following a demyelinating injury in the adult mammalian brain. Neural stem cells are an important source of oligodendrocytes in the adult brain; however, there are considerable differences in oligodendrogenesis from neural stem cells residing in different areas of the adult brain. Amongst the distinct niches containing neural stem cells, the subventricular zone lining the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus are considered the principle areas of adult neurogenesis. In addition to these areas, radial glia-like cells, which are the precursors of neural stem cells, are found in the lining of the third ventricle, where they are called tanycytes, and in the cerebellum, where they are called Bergmann glia. In this review, we will describe the contribution and regulation of each of these niches in adult oligodendrogenesis.
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20
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Seng C, Luo W, Földy C. Circuit formation in the adult brain. Eur J Neurosci 2022; 56:4187-4213. [PMID: 35724981 PMCID: PMC9546018 DOI: 10.1111/ejn.15742] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 11/30/2022]
Abstract
Neurons in the mammalian central nervous system display an enormous capacity for circuit formation during development but not later in life. In principle, new circuits could be also formed in adult brain, but the absence of the developmental milieu and the presence of growth inhibition and hundreds of working circuits are generally viewed as unsupportive for such a process. Here, we bring together evidence from different areas of neuroscience—such as neurological disorders, adult‐brain neurogenesis, innate behaviours, cell grafting, and in vivo cell reprogramming—which demonstrates robust circuit formation in adult brain. In some cases, adult‐brain rewiring is ongoing and required for certain types of behaviour and memory, while other cases show significant promise for brain repair in disease models. Together, these examples highlight that the adult brain has higher capacity for structural plasticity than previously recognized. Understanding the underlying mechanisms behind this retained plasticity has the potential to advance basic knowledge regarding the molecular organization of synaptic circuits and could herald a new era of neural circuit engineering for therapeutic repair.
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Affiliation(s)
- Charlotte Seng
- Laboratory of Neural Connectivity, Brain Research Institute, Faculties of Medicine and Science, University of Zurich, Zürich, Switzerland
| | - Wenshu Luo
- Laboratory of Neural Connectivity, Brain Research Institute, Faculties of Medicine and Science, University of Zurich, Zürich, Switzerland
| | - Csaba Földy
- Laboratory of Neural Connectivity, Brain Research Institute, Faculties of Medicine and Science, University of Zurich, Zürich, Switzerland
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21
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Haseeb M, Javaid N, Yasmeen F, Jeong U, Han JH, Yoon J, Seo JY, Heo JK, Shin HC, Kim MS, Kim W, Choi S. Novel Small-Molecule Inhibitor of NLRP3 Inflammasome Reverses Cognitive Impairment in an Alzheimer's Disease Model. ACS Chem Neurosci 2022; 13:818-833. [PMID: 35196855 DOI: 10.1021/acschemneuro.1c00831] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Aberrant activation of the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays an essential role in multiple diseases, including Alzheimer's disease (AD) and psoriasis. We report a novel small-molecule inhibitor, NLRP3-inhibitory compound 7 (NIC7), and its derivative, which inhibit NLRP3-mediated activation of caspase 1 along with the secretion of interleukin (IL)-1β, IL-18, and lactate dehydrogenase. We examined the therapeutic potential of NIC7 in a disease model of AD by analyzing its effect on cognitive impairment as well as the expression of dopamine receptors and neuronal markers. NIC7 significantly reversed the associated disease symptoms in the mice model. On the other hand, NIC7 did not reverse the disease symptoms in the imiquimod (IMQ)-induced disease model of psoriasis. This indicates that IMQ-based psoriasis is independent of NLRP3. Overall, NIC7 and its derivative have therapeutic prospects to treat AD or NLRP3-mediated diseases.
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Affiliation(s)
- Muhammad Haseeb
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
- S&K Therapeutics, Ajou University Campus Plaza 418, 199 Worldcup-ro, Yeongtong-gu, Suwon 16502, Korea
| | - Nasir Javaid
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
| | - Farzana Yasmeen
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
| | - Uisuk Jeong
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
- S&K Therapeutics, Ajou University Campus Plaza 418, 199 Worldcup-ro, Yeongtong-gu, Suwon 16502, Korea
| | - Ji Hye Han
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
| | - Juhwan Yoon
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
| | - Jee Yeon Seo
- Whan In Pharmaceutical Co., Ltd., 11, Beobwon-ro 6-gil, Songpa-gu, Seoul 05855, Korea
| | - Jae Kyung Heo
- Whan In Pharmaceutical Co., Ltd., 11, Beobwon-ro 6-gil, Songpa-gu, Seoul 05855, Korea
| | - Ho Chul Shin
- Whan In Pharmaceutical Co., Ltd., 11, Beobwon-ro 6-gil, Songpa-gu, Seoul 05855, Korea
| | - Moon Suk Kim
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
| | - Wook Kim
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
- S&K Therapeutics, Ajou University Campus Plaza 418, 199 Worldcup-ro, Yeongtong-gu, Suwon 16502, Korea
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22
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Kim CK, Sachdev PS, Braidy N. Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet? Aging Dis 2022; 13:175-214. [PMID: 35111369 PMCID: PMC8782556 DOI: 10.14336/ad.2021.0705] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022] Open
Abstract
Owing to the global exponential increase in population ageing, there is an urgent unmet need to develop reliable strategies to slow down and delay the ageing process. Age-related neurodegenerative diseases are among the main causes of morbidity and mortality in our contemporary society and represent a major socio-economic burden. There are several controversial factors that are thought to play a causal role in brain ageing which are continuously being examined in experimental models. Among them are oxidative stress and brain inflammation which are empirical to brain ageing. Although some candidate drugs have been developed which reduce the ageing phenotype, their clinical translation is limited. There are several strategies currently in development to improve brain ageing. These include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD+) levels, removal of senescent cells, 'young blood' transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological lifestyle strategies. Several studies have shown that these strategies can not only improve brain ageing by attenuating age-related neurodegenerative disease mechanisms, but also maintain cognitive function in a variety of pre-clinical experimental murine models. However, clinical evidence is limited and many of these strategies are awaiting findings from large-scale clinical trials which are nascent in the current literature. Further studies are needed to determine their long-term efficacy and lack of adverse effects in various tissues and organs to gain a greater understanding of their potential beneficial effects on brain ageing and health span in humans.
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Affiliation(s)
- Chul-Kyu Kim
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Perminder S Sachdev
- Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
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23
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Penning A, Tosoni G, Abiega O, Bielefeld P, Gasperini C, De Pietri Tonelli D, Fitzsimons CP, Salta E. Adult Neural Stem Cell Regulation by Small Non-coding RNAs: Physiological Significance and Pathological Implications. Front Cell Neurosci 2022; 15:781434. [PMID: 35058752 PMCID: PMC8764185 DOI: 10.3389/fncel.2021.781434] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/09/2021] [Indexed: 01/11/2023] Open
Abstract
The adult neurogenic niches are complex multicellular systems, receiving regulatory input from a multitude of intracellular, juxtacrine, and paracrine signals and biological pathways. Within the niches, adult neural stem cells (aNSCs) generate astrocytic and neuronal progeny, with the latter predominating in physiological conditions. The new neurons generated from this neurogenic process are functionally linked to memory, cognition, and mood regulation, while much less is known about the functional contribution of aNSC-derived newborn astrocytes and adult-born oligodendrocytes. Accumulating evidence suggests that the deregulation of aNSCs and their progeny can impact, or can be impacted by, aging and several brain pathologies, including neurodevelopmental and mood disorders, neurodegenerative diseases, and also by insults, such as epileptic seizures, stroke, or traumatic brain injury. Hence, understanding the regulatory underpinnings of aNSC activation, differentiation, and fate commitment could help identify novel therapeutic avenues for a series of pathological conditions. Over the last two decades, small non-coding RNAs (sncRNAs) have emerged as key regulators of NSC fate determination in the adult neurogenic niches. In this review, we synthesize prior knowledge on how sncRNAs, such as microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), may impact NSC fate determination in the adult brain and we critically assess the functional significance of these events. We discuss the concepts that emerge from these examples and how they could be used to provide a framework for considering aNSC (de)regulation in the pathogenesis and treatment of neurological diseases.
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Affiliation(s)
- Amber Penning
- Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
| | - Giorgia Tosoni
- Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
| | - Oihane Abiega
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Pascal Bielefeld
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Caterina Gasperini
- Neurobiology of miRNAs Lab, Istituto Italiano di Tecnologia, Genova, Italy
| | | | - Carlos P. Fitzsimons
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Evgenia Salta
- Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
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24
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Neurospheres obtained from the ciliary margin of the chicken eye possess positional values and retinal ganglion cells differentiated from them respond to EphA/ephrin-A system. Exp Eye Res 2022; 217:108965. [DOI: 10.1016/j.exer.2022.108965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 12/14/2021] [Accepted: 01/25/2022] [Indexed: 11/23/2022]
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25
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Aberle T, Piefke S, Hillgärtner S, Tamm ER, Wegner M, Küspert M. OUP accepted manuscript. Nucleic Acids Res 2022; 50:1951-1968. [PMID: 35137157 PMCID: PMC8887482 DOI: 10.1093/nar/gkac042] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/21/2021] [Accepted: 01/14/2022] [Indexed: 11/14/2022] Open
Abstract
In oligodendrocytes of the vertebrate central nervous system a complex network of transcriptional regulators is required to ensure correct and timely myelination of neuronal axons. Here we identify Zfp276, the only mammalian ZAD-domain containing zinc finger protein, as a transcriptional regulator of oligodendrocyte differentiation and central myelination downstream of Sox10. In the central nervous system, Zfp276 is exclusively expressed in mature oligodendrocytes. Oligodendroglial deletion of Zfp276 led to strongly reduced expression of myelin genes in the early postnatal mouse spinal cord. Retroviral overexpression of Zfp276 in cultured oligodendrocyte precursor cells induced precocious expression of maturation markers and myelin genes, further supporting its role in oligodendroglial differentiation. On the molecular level, Zfp276 directly binds to and represses Sox10-dependent gene regulatory regions of immaturity factors and functionally interacts with the transcriptional repressor Zeb2 to enable fast transition of oligodendrocytes to the myelinating stage.
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Affiliation(s)
- Tim Aberle
- Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054, Erlangen, Germany
| | - Sandra Piefke
- Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054, Erlangen, Germany
| | - Simone Hillgärtner
- Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054, Erlangen, Germany
| | - Ernst R Tamm
- Institut für Humananatomie und Embryologie, Universität Regensburg, D-93053, Regensburg, Germany
| | - Michael Wegner
- Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054, Erlangen, Germany
| | - Melanie Küspert
- To whom correspondence should be addressed. Tel: +49 9131 85 24638; Fax: +49 9131 85 22484;
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26
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Parkitny L, Maletic-Savatic M. Glial PAMPering and DAMPening of Adult Hippocampal Neurogenesis. Brain Sci 2021; 11:1299. [PMID: 34679362 PMCID: PMC8533961 DOI: 10.3390/brainsci11101299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 09/16/2021] [Accepted: 09/22/2021] [Indexed: 12/24/2022] Open
Abstract
Adult neurogenesis represents a mature brain's capacity to integrate newly generated neurons into functional circuits. Impairment of neurogenesis contributes to the pathophysiology of various mood and cognitive disorders such as depression and Alzheimer's Disease. The hippocampal neurogenic niche hosts neural progenitors, glia, and vasculature, which all respond to intrinsic and environmental cues, helping determine their current state and ultimate fate. In this article we focus on the major immune communication pathways and mechanisms through which glial cells sense, interact with, and modulate the neurogenic niche. We pay particular attention to those related to the sensing of and response to innate immune danger signals. Receptors for danger signals were first discovered as a critical component of the innate immune system response to pathogens but are now also recognized to play a crucial role in modulating non-pathogenic sterile inflammation. In the neurogenic niche, viable, stressed, apoptotic, and dying cells can activate danger responses in neuroimmune cells, resulting in neuroprotection or neurotoxicity. Through these mechanisms glial cells can influence hippocampal stem cell fate, survival, neuronal maturation, and integration. Depending on the context, such responses may be appropriate and on-target, as in the case of learning-associated synaptic pruning, or excessive and off-target, as in neurodegenerative disorders.
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Affiliation(s)
- Luke Parkitny
- Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA;
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27
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Samoilova EM, Belopasov VV, Baklaushev VP. Transcription Factors of Direct Neuronal Reprogramming in Ontogenesis and Ex Vivo. Mol Biol 2021; 55:645-669. [DOI: 10.1134/s0026893321040087] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 03/07/2025]
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28
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Vasan L, Park E, David LA, Fleming T, Schuurmans C. Direct Neuronal Reprogramming: Bridging the Gap Between Basic Science and Clinical Application. Front Cell Dev Biol 2021; 9:681087. [PMID: 34291049 PMCID: PMC8287587 DOI: 10.3389/fcell.2021.681087] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/02/2021] [Indexed: 12/15/2022] Open
Abstract
Direct neuronal reprogramming is an innovative new technology that involves the conversion of somatic cells to induced neurons (iNs) without passing through a pluripotent state. The capacity to make new neurons in the brain, which previously was not achievable, has created great excitement in the field as it has opened the door for the potential treatment of incurable neurodegenerative diseases and brain injuries such as stroke. These neurological disorders are associated with frank neuronal loss, and as new neurons are not made in most of the adult brain, treatment options are limited. Developmental biologists have paved the way for the field of direct neuronal reprogramming by identifying both intrinsic cues, primarily transcription factors (TFs) and miRNAs, and extrinsic cues, including growth factors and other signaling molecules, that induce neurogenesis and specify neuronal subtype identities in the embryonic brain. The striking observation that postmitotic, terminally differentiated somatic cells can be converted to iNs by mis-expression of TFs or miRNAs involved in neural lineage development, and/or by exposure to growth factors or small molecule cocktails that recapitulate the signaling environment of the developing brain, has opened the door to the rapid expansion of new neuronal reprogramming methodologies. Furthermore, the more recent applications of neuronal lineage conversion strategies that target resident glial cells in situ has expanded the clinical potential of direct neuronal reprogramming techniques. Herein, we present an overview of the history, accomplishments, and therapeutic potential of direct neuronal reprogramming as revealed over the last two decades.
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Affiliation(s)
- Lakshmy Vasan
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Eunjee Park
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Luke Ajay David
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Taylor Fleming
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
| | - Carol Schuurmans
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
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29
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Flor-García M, Ávila J, Llorens-Martín M. GSK-3β S9A overexpression leads murine hippocampal neural precursors to acquire an astroglial phenotype in vivo. Dev Neurobiol 2021; 81:710-723. [PMID: 33955712 DOI: 10.1002/dneu.22823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 03/23/2021] [Accepted: 04/07/2021] [Indexed: 11/09/2022]
Abstract
The addition of new neurons to the existing hippocampal circuitry persists in the adult dentate gyrus (DG). During this process, named adult hippocampal neurogenesis (AHN), adult hippocampal progenitor cells (AHPs) give rise to newborn dentate granule cells (DGCs). The acquisition of a neuronal lineage by AHPs is tightly regulated by numerous signaling molecules and transcription factors. In this regard, glycogen synthase kinase 3β (GSK-3β) is a master regulator of the maturation of AHPs in vitro. Here we analyzed the cell-autonomous effects of overexpressing a constitutively active form of GSK-3β (GSK-3β S9A) in AHPs in vivo. To this end, we stereotaxically injected a GSK-3β S9A-encoding retrovirus (GSK-3β-V5) into the DG of young adult C57BL6/J Ola Hsd female mice and studied the cell lineage acquisition, migratory and marker expression patterns, and the morphological maturation of the infected cells over time. Strikingly, GSK-3β S9A-transduced cells expressed glial fibrillary acidic protein (GFAP) and NG2, thereby acquiring an immature astroglial phenotype, which differed markedly from the neuronal phenotype observed in cells transduced with a control retrovirus that encoded GFP. Accordingly, the morphology and migration patterns of cells transduced by the two retroviruses are remarkably divergent. These observations support the role of GSK-3β as a cornerstone that regulates the balance between new astocytes/neurons generated in the adult murine DG.
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Affiliation(s)
- Miguel Flor-García
- Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa", CBMSO, CSIC-UAM, Madrid, Spain.,Department of Molecular Biology, Faculty of Sciences, Universidad Autónoma de Madrid, Madrid, Spain.,Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Jesús Ávila
- Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa", CBMSO, CSIC-UAM, Madrid, Spain.,Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - María Llorens-Martín
- Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa", CBMSO, CSIC-UAM, Madrid, Spain.,Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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30
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Formation and integration of new neurons in the adult hippocampus. Nat Rev Neurosci 2021; 22:223-236. [PMID: 33633402 DOI: 10.1038/s41583-021-00433-z] [Citation(s) in RCA: 164] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2021] [Indexed: 01/31/2023]
Abstract
Neural stem cells (NSCs) generate new neurons throughout life in the mammalian brain. Adult-born neurons shape brain function, and endogenous NSCs could potentially be harnessed for brain repair. In this Review, focused on hippocampal neurogenesis in rodents, we highlight recent advances in the field based on novel technologies (including single-cell RNA sequencing, intravital imaging and functional observation of newborn cells in behaving mice) and characterize the distinct developmental steps from stem cell activation to the integration of newborn neurons into pre-existing circuits. Further, we review current knowledge of how levels of neurogenesis are regulated, discuss findings regarding survival and maturation of adult-born cells and describe how newborn neurons affect brain function. The evidence arguing for (and against) lifelong neurogenesis in the human hippocampus is briefly summarized. Finally, we provide an outlook of what is needed to improve our understanding of the mechanisms and functional consequences of adult neurogenesis and how the field may move towards more translational relevance in the context of acute and chronic neural injury and stem cell-based brain repair.
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31
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Oproescu AM, Han S, Schuurmans C. New Insights Into the Intricacies of Proneural Gene Regulation in the Embryonic and Adult Cerebral Cortex. Front Mol Neurosci 2021; 14:642016. [PMID: 33658912 PMCID: PMC7917194 DOI: 10.3389/fnmol.2021.642016] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 01/26/2021] [Indexed: 12/21/2022] Open
Abstract
Historically, the mammalian brain was thought to lack stem cells as no new neurons were found to be made in adulthood. That dogma changed ∼25 years ago with the identification of neural stem cells (NSCs) in the adult rodent forebrain. However, unlike rapidly self-renewing mature tissues (e.g., blood, intestinal crypts, skin), the majority of adult NSCs are quiescent, and those that become 'activated' are restricted to a few neurogenic zones that repopulate specific brain regions. Conversely, embryonic NSCs are actively proliferating and neurogenic. Investigations into the molecular control of the quiescence-to-proliferation-to-differentiation continuum in the embryonic and adult brain have identified proneural genes encoding basic-helix-loop-helix (bHLH) transcription factors (TFs) as critical regulators. These bHLH TFs initiate genetic programs that remove NSCs from quiescence and drive daughter neural progenitor cells (NPCs) to differentiate into specific neural cell subtypes, thereby contributing to the enormous cellular diversity of the adult brain. However, new insights have revealed that proneural gene activities are context-dependent and tightly regulated. Here we review how proneural bHLH TFs are regulated, with a focus on the murine cerebral cortex, drawing parallels where appropriate to other organisms and neural tissues. We discuss upstream regulatory events, post-translational modifications (phosphorylation, ubiquitinylation), protein-protein interactions, epigenetic and metabolic mechanisms that govern bHLH TF expression, stability, localization, and consequent transactivation of downstream target genes. These tight regulatory controls help to explain paradoxical findings of changes to bHLH activity in different cellular contexts.
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Affiliation(s)
- Ana-Maria Oproescu
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Sisu Han
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Carol Schuurmans
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
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32
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An Angiotensin-Responsive Connection from the Lamina Terminalis to the Paraventricular Nucleus of the Hypothalamus Evokes Vasopressin Secretion to Increase Blood Pressure in Mice. J Neurosci 2020; 41:1429-1442. [PMID: 33328294 DOI: 10.1523/jneurosci.1600-20.2020] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 11/29/2020] [Accepted: 12/03/2020] [Indexed: 12/22/2022] Open
Abstract
Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.SIGNIFICANCE STATEMENT Hypertension is a widespread health problem and risk factor for cardiovascular disease. Although treatments exist, a substantial percentage of patients suffer from "drug-resistant" hypertension, a condition associated with increased activation of brain angiotensin receptors, enhanced sympathetic nervous system activity, and elevated vasopressin levels. The present study highlights a role for angiotensin Type 1a receptor expressing neurons located within the lamina terminalis in regulating endocrine and behavioral responses that are involved in maintaining cardiovascular homeostasis. More specifically, data presented here reveal functional excitatory connections between angiotensin-sensitive neurons in the lamina terminals and vasopressin neurons in the paraventricular nucleus of the hypothalamus, and further indicate that activation of this circuit raises blood pressure. These neurons may be a promising target for antihypertensive therapeutics.
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33
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Mal’tsev DI, Podgornyi OV. Molecular and Cellular Mechanisms Regulating Quiescence and Division of Hippocampal Stem Cells. NEUROCHEM J+ 2020. [DOI: 10.1134/s1819712420040054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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34
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DCX + neuronal progenitors contribute to new oligodendrocytes during remyelination in the hippocampus. Sci Rep 2020; 10:20095. [PMID: 33208869 PMCID: PMC7674453 DOI: 10.1038/s41598-020-77115-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 11/02/2020] [Indexed: 02/07/2023] Open
Abstract
A pool of different types of neural progenitor cells resides in the adult hippocampus. Apart from doublecortin-expressing (DCX+) neuronal progenitor cells (NPCs), the hippocampal parenchyma also contains oligodendrocyte precursor cells (OPCs), which can differentiate into myelinating oligodendrocytes. It is not clear yet to what extent the functions of these different progenitor cell types overlap and how plastic these cells are in response to pathological processes. The aim of this study was to investigate whether hippocampal DCX+ NPCs can generate new oligodendrocytes under conditions in which myelin repair is required. For this, the cell fate of DCX-expressing NPCs was analyzed during cuprizone-induced demyelination and subsequent remyelination in two regions of the hippocampal dentate gyrus of DCX-CreERT2/Flox-EGFP transgenic mice. In this DCX reporter model, the number of GFP+ NPCs co-expressing Olig2 and CC1, a combination of markers typically found in mature oligodendrocytes, was significantly increased in the hippocampal DG during remyelination. In contrast, the numbers of GFP+PDGFRα+ cells, as well as their proliferation, were unaffected by de- or remyelination. During remyelination, a higher portion of newly generated BrdU-labeled cells were GFP+ NPCs and there was an increase in new oligodendrocytes derived from these proliferating cells (GFP+Olig2+BrdU+). These results suggest that DCX-expressing NPCs were able to contribute to the generation of mature oligodendrocytes during remyelination in the adult hippocampus.
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35
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Quantitative characterization of proliferative cells subpopulations in the hilus of the hippocampus of adult Wistar rats: an integrative study. J Mol Histol 2020; 51:437-453. [PMID: 32653982 DOI: 10.1007/s10735-020-09895-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
Abstract
The hilus plays an important role modulating the excitability of the hippocampal dentate gyrus (DG). It also harbors proliferative cells whose proliferation rate is modified during pathological events. However, the characterization of these cells, in terms of cellular identity, lineage, and fate, as well as the morphology and proportion of each cell subpopulation has been poorly studied. Therefore, a deeper investigation of hilar proliferative cells might expand the knowledge not only in the physiology, but in the pathophysiological processes related to the hippocampus too. The aim of this work was to perform an integrative study characterizing the identity of proliferative cells populations harbored in the hilus, along with morphology and proportion. In addition, this study provides comparative evidence of the subgranular zone (SGZ) of the DG. Quantified cells included proliferative, neural precursor, Type 1, oligodendrocyte progenitor (OPCs), neural progenitor (NPCs), and proliferative mature astrocytes in the hilus and SGZ of Wistar adult rats. Our results showed that 84% of the hilar proliferative cells correspond to neural precursor cells, OPCs and NPCs being the most abundant at 54 and 45%, respectively, unlike the SGZ, where OPCs represent only 11%. Proliferative mature astrocytes and Type 1-like cells were rarely observed in the hilus. Together, our results lay the basis for future studies focused on the lineage and fate of hilar proliferative cells and suggest that the hilus could be relevant to the formation of new cells that modulate multiple physiological processes governed by the hippocampus.
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36
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Niklison-Chirou MV, Agostini M, Amelio I, Melino G. Regulation of Adult Neurogenesis in Mammalian Brain. Int J Mol Sci 2020; 21:ijms21144869. [PMID: 32660154 PMCID: PMC7402357 DOI: 10.3390/ijms21144869] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/02/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022] Open
Abstract
Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways. Here, we review recent findings that advance our knowledge in epigenetic, transcriptional and metabolic regulation of adult neurogenesis in the SGZ of the hippocampus, with a special attention to the p53-family of transcription factors.
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Affiliation(s)
- Maria Victoria Niklison-Chirou
- Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, UK;
- Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
| | - Massimiliano Agostini
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133 Rome, Italy; (M.A.); (I.A.)
| | - Ivano Amelio
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133 Rome, Italy; (M.A.); (I.A.)
- School of Life Sciences, University of Nottingham, Nottingham NG7 2HU, UK
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133 Rome, Italy; (M.A.); (I.A.)
- Correspondence:
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Spinelli M, Fusco S, Grassi C. Brain insulin resistance impairs hippocampal plasticity. VITAMINS AND HORMONES 2020; 114:281-306. [PMID: 32723548 DOI: 10.1016/bs.vh.2020.04.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nutrient-related signals have been demonstrated to influence brain development and cognitive functions. In particular, insulin signaling has been shown to impact on molecular cascades underlying hippocampal plasticity, learning and memory. Alteration of brain insulin signaling interferes with the maintenance of neural stem cell niche and neuronal activity in the hippocampus. Brain insulin resistance is also emerging as key factor causing the cognitive impairment observed in metabolic and neurodegenerative diseases. Here, we review the molecular mechanisms involved in the insulin modulation of both adult neurogenesis and synaptic activity in the hippocampus. We also summarize the effects of altered insulin sensitivity on hippocampal plasticity. Finally, we reassume the experimental and epidemiological evidence highlighting the critical role of brain insulin resistance at the crossroad between type 2 diabetes and Alzheimer's disease.
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Affiliation(s)
- Matteo Spinelli
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Salvatore Fusco
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
| | - Claudio Grassi
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
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Secretome Analysis of Mesenchymal Stem Cell Factors Fostering Oligodendroglial Differentiation of Neural Stem Cells In Vivo. Int J Mol Sci 2020; 21:ijms21124350. [PMID: 32570968 PMCID: PMC7352621 DOI: 10.3390/ijms21124350] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/14/2020] [Accepted: 06/16/2020] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach.
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Flitsch LJ, Laupman KE, Brüstle O. Transcription Factor-Based Fate Specification and Forward Programming for Neural Regeneration. Front Cell Neurosci 2020; 14:121. [PMID: 32508594 PMCID: PMC7251072 DOI: 10.3389/fncel.2020.00121] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 04/14/2020] [Indexed: 12/11/2022] Open
Abstract
Traditionally, in vitro generation of donor cells for brain repair has been dominated by the application of extrinsic growth factors and morphogens. Recent advances in cell engineering strategies such as reprogramming of somatic cells into induced pluripotent stem cells and direct cell fate conversion have impressively demonstrated the feasibility to manipulate cell identities by the overexpression of cell fate-determining transcription factors. These strategies are now increasingly implemented for transcription factor-guided differentiation of neural precursors and forward programming of pluripotent stem cells toward specific neural subtypes. This review covers major achievements, pros and cons, as well as future prospects of transcription factor-based cell fate specification and the applicability of these approaches for the generation of donor cells for brain repair.
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Affiliation(s)
- Lea J Flitsch
- Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany
| | - Karen E Laupman
- Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany
| | - Oliver Brüstle
- Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany
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40
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Aprato J, Sock E, Weider M, Elsesser O, Fröb F, Wegner M. Myrf guides target gene selection of transcription factor Sox10 during oligodendroglial development. Nucleic Acids Res 2020; 48:1254-1270. [PMID: 31828317 PMCID: PMC7026603 DOI: 10.1093/nar/gkz1158] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/25/2019] [Accepted: 11/28/2019] [Indexed: 12/13/2022] Open
Abstract
Oligodendrocytes generate myelin in the vertebrate central nervous system and thus ensure rapid propagation of neuronal activity. Their development is controlled by a network of transcription factors that function as determinants of cell identity or as temporally restricted stage-specific regulators. The continuously expressed Sox10 and Myrf, a factor induced during late development, are particularly important for terminal differentiation. How these factors function together mechanistically and influence each other, is not well understood. Here we show that Myrf not only cooperates with Sox10 during the induction of genes required for differentiation and myelin formation. Myrf also inhibits the activity of Sox10 on genes that are essential during earlier phases of oligodendroglial development. By characterization of the exact DNA-binding requirements of Myrf, we furthermore show that cooperative activation is a consequence of joint binding of Sox10 and Myrf to the same regulatory regions. In contrast, inhibition of Sox10-dependent gene activation occurs on genes that lack Myrf binding sites and likely involves physical interaction between Myrf and Sox10 followed by sequestration. These two opposite activities allow Myrf to redirect Sox10 from genes that it activates in oligodendrocyte precursor cells to genes that need to be induced during terminal differentiation.
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Affiliation(s)
- Jessica Aprato
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Elisabeth Sock
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Matthias Weider
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Olga Elsesser
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Franziska Fröb
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Wegner
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- To whom correspondence should be addressed. Tel: +49 9131 85 24620;
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41
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Quiescent Neural Stem Cells for Brain Repair and Regeneration: Lessons from Model Systems. Trends Neurosci 2020; 43:213-226. [PMID: 32209453 DOI: 10.1016/j.tins.2020.02.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/26/2020] [Accepted: 02/05/2020] [Indexed: 12/29/2022]
Abstract
Neural stem cells (NSCs) are multipotent progenitors that are responsible for producing all of the neurons and macroglia in the nervous system. In adult mammals, NSCs reside predominantly in a mitotically dormant, quiescent state, but they can proliferate in response to environmental inputs such as feeding or exercise. It is hoped that quiescent NSCs could be activated therapeutically to contribute towards repair in humans. This will require an understanding of quiescent NSC heterogeneities and regulation during normal physiology and following brain injury. Non-mammalian vertebrates (zebrafish and salamanders) and invertebrates (Drosophila) offer insights into brain repair and quiescence regulation that are difficult to obtain using rodent models alone. We review conceptual progress from these various models, a first step towards harnessing quiescent NSCs for therapeutic purposes.
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Sumners C, Alleyne A, Rodríguez V, Pioquinto DJ, Ludin JA, Kar S, Winder Z, Ortiz Y, Liu M, Krause EG, de Kloet AD. Brain angiotensin type-1 and type-2 receptors: cellular locations under normal and hypertensive conditions. Hypertens Res 2019; 43:281-295. [PMID: 31853042 DOI: 10.1038/s41440-019-0374-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 10/25/2019] [Accepted: 11/02/2019] [Indexed: 12/15/2022]
Abstract
Brain angiotensin-II (Ang-II) type-1 receptors (AT1Rs), which exert profound effects on normal cardiovascular, fluid, and metabolic homeostasis, are overactivated in and contribute to chronic sympathoexcitation and hypertension. Accumulating evidence indicates that the activation of Ang-II type-2 receptors (AT2Rs) in the brain exerts effects that are opposite to those of AT1Rs, lowering blood pressure, and reducing hypertension. Thus, it would be interesting to understand the relative cellular localization of AT1R and AT2R in the brain under normal conditions and whether this localization changes during hypertension. Here, we developed a novel AT1aR-tdTomato reporter mouse strain in which the location of brain AT1aR was largely consistent with that determined in the previous studies. This AT1aR-tdTomato reporter mouse strain was crossed with our previously described AT2R-eGFP reporter mouse strain to yield a novel dual AT1aR/AT2R reporter mouse strain, which allowed us to determine that AT1aR and AT2R are primarily localized to different populations of neurons in brain regions controlling cardiovascular, fluid, and metabolic homeostasis. Using the individual AT1aR-tdTomato reporter mice, we also demonstrated that during hypertension induced by the administration of deoxycorticosterone acetate-salt, there was no shift in the expression of AT1aR from neurons to microglia or astrocytes in the paraventricular nucleus, a brain area important for sympathetic regulation. Using AT2R-eGFP reporter mice under similar hypertensive conditions, we demonstrated that the same was true of AT2R expression in the nucleus of the solitary tract (NTS), an area critical for baroreflex control. Collectively, these findings provided a novel means to assess the colocalization of AT1R and AT2R in the brain and a novel view of their cellular localization in hypertension.
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Affiliation(s)
- Colin Sumners
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Amy Alleyne
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Vermalí Rodríguez
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - David J Pioquinto
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Jacob A Ludin
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Shormista Kar
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Zachary Winder
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, 32611, USA.,Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Yuma Ortiz
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Meng Liu
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Eric G Krause
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Annette D de Kloet
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, 32611, USA.
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Wegleiter T, Buthey K, Gonzalez-Bohorquez D, Hruzova M, Bin Imtiaz MK, Abegg A, Mebert I, Molteni A, Kollegger D, Pelczar P, Jessberger S. Palmitoylation of BMPR1a regulates neural stem cell fate. Proc Natl Acad Sci U S A 2019; 116:25688-25696. [PMID: 31772009 PMCID: PMC6926058 DOI: 10.1073/pnas.1912671116] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Neural stem cells (NSCs) generate neurons and glial cells throughout embryonic and postnatal brain development. The role of S-palmitoylation (also referred to as S-acylation), a reversible posttranslational lipid modification of proteins, in regulating the fate and activity of NSCs remains largely unknown. We used an unbiased screening approach to identify proteins that are S-acylated in mouse NSCs and showed that bone morphogenic protein receptor 1a (BMPR1a), a core mediator of BMP signaling, is palmitoylated. Genetic manipulation of S-acylated sites affects the localization and trafficking of BMPR1a and leads to altered BMP signaling. Strikingly, defective palmitoylation of BMPR1a modulates NSC function within the mouse brain, resulting in enhanced oligodendrogenesis. Thus, we identified a mechanism regulating the behavior of NSCs and provided the framework to characterize dynamic posttranslational lipid modifications of proteins in the context of NSC biology.
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Affiliation(s)
- Thomas Wegleiter
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland;
| | - Kilian Buthey
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland
| | - Daniel Gonzalez-Bohorquez
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland
| | - Martina Hruzova
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland
| | - Muhammad Khadeesh Bin Imtiaz
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland
| | - Andrin Abegg
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland
| | - Iliana Mebert
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland
| | - Adriano Molteni
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland
| | - Dominik Kollegger
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland
| | - Pawel Pelczar
- Center for Transgenic Models, University of Basel, 4001 Basel, Switzerland
| | - Sebastian Jessberger
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland;
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Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis? Cells 2019; 8:cells8121591. [PMID: 31817891 PMCID: PMC6953000 DOI: 10.3390/cells8121591] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/28/2019] [Accepted: 12/04/2019] [Indexed: 12/25/2022] Open
Abstract
Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID). Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS, but underestimated the role of glial cells as pathogenic players. Aberrant or impaired differentiation within the oligodendroglial lineage and altered white matter functionality are thought to contribute to central nervous system (CNS) malformations. Given that white matter, comprised of oligodendrocytes and their myelin sheaths, is vital for higher brain function, gathering knowledge about pathways and modulators challenging oligodendrogenesis and cell lineages within DS is essential. This review article discusses to what degree DS-related effects on oligodendroglial cells have been described and presents collected evidence regarding induced cell-fate switches, thereby resulting in an enhanced generation of astrocytes. Moreover, alterations in white matter formation observed in mouse and human post-mortem brains are described. Finally, the rationale for a better understanding of pathways and modulators responsible for the glial cell imbalance as a possible source for future therapeutic interventions is given based on current experience on pro-oligodendroglial treatment approaches developed for demyelinating diseases, such as multiple sclerosis.
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45
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Traxler L, Edenhofer F, Mertens J. Next-generation disease modeling with direct conversion: a new path to old neurons. FEBS Lett 2019; 593:3316-3337. [PMID: 31715002 PMCID: PMC6907729 DOI: 10.1002/1873-3468.13678] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/20/2019] [Accepted: 11/07/2019] [Indexed: 12/13/2022]
Abstract
Within just over a decade, human reprogramming-based disease modeling has developed from a rather outlandish idea into an essential part of disease research. While iPSCs are a valuable tool for modeling developmental and monogenetic disorders, their rejuvenated identity poses limitations for modeling age-associated diseases. Direct cell-type conversion of fibroblasts into induced neurons (iNs) circumvents rejuvenation and preserves hallmarks of cellular aging. iNs are thus advantageous for modeling diseases that possess strong age-related and epigenetic contributions and can complement iPSC-based strategies for disease modeling. In this review, we provide an overview of the state of the art of direct iN conversion and describe the key epigenetic, transcriptomic, and metabolic changes that occur in converting fibroblasts. Furthermore, we summarize new insights into this fascinating process, particularly focusing on the rapidly changing criteria used to define and characterize in vitro-born human neurons. Finally, we discuss the unique features that distinguish iNs from other reprogramming-based neuronal cell models and how iNs are relevant to disease modeling.
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Affiliation(s)
- Larissa Traxler
- Department of GenomicsStem Cell Biology & Regenerative MedicineInstitute of Molecular Biology & CMBILeopold‐Franzens‐University InnsbruckInnsbruckAustria
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaCAUSA
| | - Frank Edenhofer
- Department of GenomicsStem Cell Biology & Regenerative MedicineInstitute of Molecular Biology & CMBILeopold‐Franzens‐University InnsbruckInnsbruckAustria
| | - Jerome Mertens
- Department of GenomicsStem Cell Biology & Regenerative MedicineInstitute of Molecular Biology & CMBILeopold‐Franzens‐University InnsbruckInnsbruckAustria
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaCAUSA
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46
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Yavarpour‐Bali H, Nakhaei‐Nejad M, Yazdi A, Ghasemi‐Kasman M. Direct conversion of somatic cells towards oligodendroglial lineage cells: A novel strategy for enhancement of myelin repair. J Cell Physiol 2019; 235:2023-2036. [DOI: 10.1002/jcp.29195] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 09/03/2019] [Indexed: 12/12/2022]
Affiliation(s)
| | | | - Azadeh Yazdi
- Department of Physiology, Faculty of Medical Sciences Isfahan University of Medical Sciences, Isfahan Iran
| | - Maryam Ghasemi‐Kasman
- Cellular and Molecular Biology Research Center, Health Research Institute Babol University of Medical Sciences Babol Iran
- Neuroscience Research Center, Health Research Institute Babol University of Medical Sciences Babol Iran
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47
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Gruchot J, Weyers V, Göttle P, Förster M, Hartung HP, Küry P, Kremer D. The Molecular Basis for Remyelination Failure in Multiple Sclerosis. Cells 2019; 8:cells8080825. [PMID: 31382620 PMCID: PMC6721708 DOI: 10.3390/cells8080825] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 07/31/2019] [Accepted: 08/01/2019] [Indexed: 12/13/2022] Open
Abstract
Myelin sheaths in the central nervous system (CNS) insulate axons and thereby allow saltatory nerve conduction, which is a prerequisite for complex brain function. Multiple sclerosis (MS), the most common inflammatory autoimmune disease of the CNS, leads to the destruction of myelin sheaths and the myelin-producing oligodendrocytes, thus leaving behind demyelinated axons prone to injury and degeneration. Clinically, this process manifests itself in significant neurological symptoms and disability. Resident oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) are present in the adult brain, and can differentiate into mature oligodendrocytes which then remyelinate the demyelinated axons. However, for multiple reasons, in MS the regenerative capacity of these cell populations diminishes significantly over time, ultimately leading to neurodegeneration, which currently remains untreatable. In addition, microglial cells, the resident innate immune cells of the CNS, can contribute further to inflammatory and degenerative axonal damage. Here, we review the molecular factors contributing to remyelination failure in MS by inhibiting OPC and NSC differentiation or modulating microglial behavior.
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Affiliation(s)
- Joel Gruchot
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Vivien Weyers
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Peter Göttle
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Moritz Förster
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Hans-Peter Hartung
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Patrick Küry
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - David Kremer
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
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48
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Kurtenbach S, Goss GM, Goncalves S, Choi R, Hare JM, Chaudhari N, Goldstein BJ. Cell-Based Therapy Restores Olfactory Function in an Inducible Model of Hyposmia. Stem Cell Reports 2019; 12:1354-1365. [PMID: 31155504 PMCID: PMC6565856 DOI: 10.1016/j.stemcr.2019.05.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 04/30/2019] [Accepted: 05/02/2019] [Indexed: 12/18/2022] Open
Abstract
Stem cell-based therapies have been proposed as a strategy to replace damaged tissues, especially in the nervous system. A primary sensory modality, olfaction, is impaired in 12% of the US population, but lacks treatment options. We report here the development of a novel mouse model of inducible hyposmia and demonstrate that purified tissue-specific stem cells delivered intranasally engraft to produce olfactory neurons, achieving recovery of function. Adult mice were rendered hyposmic by conditional deletion of the ciliopathy-related IFT88 gene in the olfactory sensory neuron lineage and following experimentally induced olfactory injury, received either vehicle or stem cell infusion intranasally. Engraftment-derived olfactory neurons were identified histologically, and functional improvements were measured via electrophysiology and behavioral assay. We further explored mechanisms in culture that promote expansion of engraftment-competent adult olfactory basal progenitor cells. These findings provide a basis for translational research on propagating adult tissue-specific sensory progenitor cells and testing their therapeutic potential.
A novel mouse model of inducible olfactory loss was used to test stem cell therapy Purified adult tissue-specific stem cells can engraft and restore olfaction Culture expansion of engraftment-competent stem cells was examined via RNA-seq
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Affiliation(s)
- Sarah Kurtenbach
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Biomedical Research Building, Room 809, Miami, FL 33136, USA; Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Garrett M Goss
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Biomedical Research Building, Room 809, Miami, FL 33136, USA; Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Stefania Goncalves
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Rhea Choi
- Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Graduate Program in Neurosciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Biomedical Research Building, Room 809, Miami, FL 33136, USA; Department of Medicine, Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Nirupa Chaudhari
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Graduate Program in Neurosciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Bradley J Goldstein
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Biomedical Research Building, Room 809, Miami, FL 33136, USA; Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Graduate Program in Neurosciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
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49
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Chen SH, Haam J, Walker M, Scappini E, Naughton J, Martin NP. Recombinant Viral Vectors as Neuroscience Tools. ACTA ACUST UNITED AC 2019; 87:e67. [PMID: 30901512 DOI: 10.1002/cpns.67] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Recombinant viruses are highly efficient vehicles for in vivo gene delivery. Viral vectors expand the neurobiology toolbox to include direct and rapid anterograde, retrograde, and trans-synaptic delivery of tracers, sensors, and actuators to the mammalian brain. Each viral type offers unique advantages and limitations. To establish strategies for selecting a suitable viral type, this article aims to provide readers with an overview of viral recombinant technology, viral structure, tropism, and differences between serotypes and pseudotypes for three of the most commonly used vectors in neurobiology research: adeno-associated viruses, retro/lentiviruses, and glycoprotein-deleted rabies viruses. © 2019 by John Wiley & Sons, Inc.
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Affiliation(s)
- Shih-Heng Chen
- Viral Vector Core, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina.,Neurobiology Laboratory, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
| | - Juhee Haam
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
| | - Mitzie Walker
- Viral Vector Core, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina.,Neurobiology Laboratory, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
| | - Erica Scappini
- Signal Transduction Laboratory, Fluorescence Microscopy and Imaging Center, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
| | - John Naughton
- Gene Transfer, Targeting and Therapeutics (GT3) Core, Salk Institute for Biological Studies, La Jolla, California
| | - Negin P Martin
- Viral Vector Core, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina.,Neurobiology Laboratory, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
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Chen SH, Haam J, Walker M, Scappini E, Naughton J, Martin NP. Production of Viral Constructs for Neuroanatomy, Calcium Imaging, and Optogenetics. ACTA ACUST UNITED AC 2019; 87:e66. [PMID: 30883041 DOI: 10.1002/cpns.66] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Advances in design and use of light-sensitive and light-emitting sensors have facilitated observation, measurement, and control of neuronal activities. Viruses are effective vectors for delivery of these valuable research tools to mammalian brains. Recombinant viruses are optimized to mediate regulatable, long-term, and cell-specific gene expression. Here, we describe production methods for three of the most commonly used types of recombinant viruses in neurobiology research: adeno-associated virus (AAV), retrovirus/lentivirus, and glycoprotein-deleted rabies virus. These viral constructs are frequently used for calcium imaging or to deliver neural tracers and optogenetic tools. Popular constructs are readily obtained commercially; however, customized virus production through commercial sources is time consuming and costly. This article aims to provide readers with detailed technical information for rapid production and validation of high-quality viral particles in a laboratory setting while highlighting advantages and limitations of each viral type. © 2019 by John Wiley & Sons, Inc.
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Affiliation(s)
- Shih-Heng Chen
- Viral Vector Core, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
| | - Juhee Haam
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
| | - Mitzie Walker
- Viral Vector Core, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
| | - Erica Scappini
- Signal Transduction Laboratory, Fluorescence Microscopy and Imaging Center, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
| | - John Naughton
- Gene Transfer, Targeting and Therapeutics (GT3) Core, Salk Institute for Biological Studies, La Jolla, California
| | - Negin P Martin
- Viral Vector Core, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina
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